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1. A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol

Author

Jean-Marc Treluyer, Benedicte Demeer, Laurence Faivre, Marc Bardou, Nathalie Boddaert, Paul Kuentz, Florence Petit, Christine Francannet, Pierre Vabres, Nadia Bahi-Buisson, Estelle Colin, Laurent Guibaud, Romaric Loffroy, Maxime Luu, Caroline Racine, Aurore Garde, Philippe Khau Van Kien, Aurore Curie, Nawale Hadouiri, Aurélie Espitalier, Agnès Maurer, Maud Carpentier, Adélaide Rega, Mouna Chebbi, Julie Charligny, Guillaume Canaud, Camille Fleck, Amelie Cransac, Elise Boucher-Brischoux, Adélaïde Brosseau-Beauvir, Florian Cherik, Alice Phan, Michaela Semeraro, Marion Nys, Charles Joris Roux, Alinoë Lavillaureix, and Isabelle Maruani

Subjects
Medicine
Abstract

Introduction The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS). During its development, in patients with the MCAP subgroup of PROS, there was no specific, standardised evaluation of the effect on neuro-cognitive functioning. Moreover, it remains unknown if the molecule crosses the blood-brain barrier. Our objective is to evaluate the efficacy of a 24 month treatment with alpelisib on adaptive behaviour in patients with MCAP syndrome.Methods and analysis SESAM is an industry-sponsored two-period multicentre French academic phase II trial, with a 6-month double-blind, placebo-controlled period followed by an open-label period. The primary endpoint is a ≥4-point improvement in the Vineland II Adaptive Behaviour Scale (VABS), 24 months after treatment initiation. Secondary objectives are safety, VABS improvement at 6 months, impact on the quality of life, epilepsy and hypotonia. 20 patients aged 2 to 40 years with an MCAP diagnosis and neurodevelopmental disorders of various degrees, will be followed monthly in local centres, centrally assessed (clinical, biological, neuropsychological and functional evaluation) at baseline and every 6 months. Patients will be evaluated by volumetric MRI at baseline and at 24 months. An optional lumbar puncture will be performed to investigate blood-brain barrier crossing. Inclusions were completed by April 2024, with the end of follow-up in November 2026.Given the efficacy of alpelisib in patients with PROS, if the drug crosses the blood-brain barrier, we can expect a clinical benefit for patients with neurocognitive disorders.Ethics and dissemination Ethical approval was given by CPP Sud-Ouest et Outre-Mer I (reference: 2022-500197-34-01). Findings from this study will be disseminated via publication, reports and conference presentations.Trial registration number NCT05577754

Published
2024
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2. Health-related quality of life in children and adolescents with Marfan syndrome or related disorders: a controlled cross-sectional study

Author

Thomas Edouard, Marie-Christine Picot, Fernanda Bajanca, Helena Huguet, Aitor Guitarte, Maud Langeois, Bertrand Chesneau, Philippe Khau Van Kien, Eric Garrigue, Yves Dulac, and Pascal Amedro

Subjects
Marfan syndrome, Health-related quality of life, Aerobic physical fitness, Peak oxygen consumption, Physical well-being, Psychological well-being, Medicine
Abstract

Abstract Background This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson’s or Spearman’s coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. Results Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. Conclusions This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. Trial registration ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

Published
2024
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5. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Author

Margot, Henri, Boursier, Guilaine, Duflos, Claire, Sanchez, Elodie, Amiel, Jeanne, Andrau, Jean-Christophe, Arpin, Stéphanie, Brischoux-Boucher, Elise, Boute, Odile, Burglen, Lydie, Caille, Charlotte, Capri, Yline, Collignon, Patrick, Conrad, Solène, Cormier-Daire, Valérie, Delplancq, Geoffroy, Dieterich, Klaus, Dollfus, Hélène, Fradin, Mélanie, Faivre, Laurence, Fernandes, Helder, Francannet, Christine, Gatinois, Vincent, Gerard, Marion, Goldenberg, Alice, Ghoumid, Jamal, Grotto, Sarah, Guerrot, Anne-Marie, Guichet, Agnès, Isidor, Bertrand, Jacquemont, Marie-Line, Julia, Sophie, Khau Van Kien, Philippe, Legendre, Marine, Le Quan Sang, K.H., Leheup, Bruno, Lyonnet, Stanislas, Magry, Virginie, Manouvrier, Sylvie, Martin, Dominique, Morel, Godelieve, Munnich, Arnold, Naudion, Sophie, Odent, Sylvie, Perrin, Laurence, Petit, Florence, Philip, Nicole, Rio, Marlène, Robbe, Julie, Rossi, Massimiliano, Sarrazin, Elisabeth, Toutain, Annick, Van Gils, Julien, Vera, Gabriella, Verloes, Alain, Weber, Sacha, Whalen, Sandra, Sanlaville, Damien, Lacombe, Didier, Aladjidi, Nathalie, and Geneviève, David

Published
2020
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6. A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Author

Bertrand Chesneau, Aurélie Plancke, Guillaume Rolland, Bertrand Marcheix, Yves Dulac, Thomas Edouard, Julie Plaisancié, Marion Aubert‐Mucca, Sophie Julia, Maud Langeois, Thierry Lavabre‐Bertrand, and Philippe Khau Van Kien

Subjects
genotype–phenotype correlation, heritable aortic aneurysm syndrome, MYH11, patent ductus arteriosus, splicing, Genetics, QH426-470
Abstract

Abstract Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.

Published
2021
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7. Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Author

Bertrand Chesneau, Thomas Edouard, Yves Dulac, Hélène Colineaux, Maud Langeois, Nadine Hanna, Catherine Boileau, Pauline Arnaud, Nicolas Chassaing, Sophie Julia, Guillaume Jondeau, Aurélie Plancke, Philippe Khau Van Kien, and Julie Plaisancié

Subjects
Aneurysms‐Osteoarthritis syndrome, Loeys–Dietz syndrome, SMAD3, TGFβ, Genetics, QH426-470
Abstract

Abstract Background Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants. Methods To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype‐phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type. Results We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients. Conclusion Therefore, this report brings additional data for the genotype‐phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.

Published
2020
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8. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing

Author

Kuentz, Paul, St-Onge, Judith, Duffourd, Yannis, Courcet, Jean-Benoît, Carmignac, Virginie, Jouan, Thibaud, Sorlin, Arthur, Abasq-Thomas, Claire, Albuisson, Juliette, Amiel, Jeanne, Amram, Daniel, Arpin, Stéphanie, Attie-Bitach, Tania, Bahi-Buisson, Nadia, Barbarot, Sébastien, Baujat, Geneviève, Bessis, Didier, Boccara, Olivia, Bonnière, Maryse, Boute, Odile, Bursztejn, Anne-Claire, Chiaverini, Christine, Cormier-Daire, Valérie, Coubes, Christine, Delobel, Bruno, Edery, Patrick, Chehadeh, Salima El, Francannet, Christine, Geneviève, David, Goldenberg, Alice, Haye, Damien, Isidor, Bertrand, Jacquemont, Marie-Line, Khau Van Kien, Philippe, Lacombe, Didier, Martin, Ludovic, Martinovic, Jelena, Maruani, Annabel, Mathieu-Dramard, Michèle, Mazereeuw-Hautier, Juliette, Michot, Caroline, Mignot, Cyril, Miquel, Juliette, Morice-Picard, Fanny, Petit, Florence, Phan, Alice, Rossi, Massimiliano, Touraine, Renaud, Verloes, Alain, Vincent, Marie, Vincent-Delorme, Catherine, Whalen, Sandra, Willems, Marjolaine, Marle, Nathalie, Lehalle, Daphné, Thevenon, Julien, Thauvin-Robinet, Christel, Hadj-Rabia, Smaïl, Faivre, Laurence, Vabres, Pierre, and Rivière, Jean-Baptiste

Published
2017
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10. NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients

Author

Bertacchi, Michele, Romano, Anna Lisa, Loubat, Agnès, Tran Mau‐Them, Frederic, Willems, Marjolaine, Faivre, Laurence, Khau van Kien, Philippe, Perrin, Laurence, Devillard, Françoise, Sorlin, Arthur, Kuentz, Paul, Philippe, Christophe, Garde, Aurore, Neri, Francesco, Di Giaimo, Rossella, Oliviero, Salvatore, Cappello, Silvia, D'Incerti, Ludovico, Frassoni, Carolina, and Studer, Michèle

Published
2020
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11. Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule

Author

Cayrefourcq, Laure, Vincent, Marie-Claire, Pierredon, Sandra, Moutou, Céline, Imbert-Bouteille, Marion, Haquet, Emmanuelle, Puechberty, Jacques, Willems, Marjolaine, Liautard-Haag, Cathy, Molinari, Nicolas, Zordan, Cécile, Dorian, Virginie, Rooryck-Thambo, Caroline, Goizet, Cyril, Chaussenot, Annabelle, Rouzier, Cécile, Boureau-Wirth, Amandine, Monteil, Laetitia, Calvas, Patrick, Miry, Claire, Favre, Romain, Petrov, Yuliya, Khau Van Kien, Philippe, Le Boette, Elsa, Fradin, Mélanie, Alix-Panabières, Catherine, and Guissart, Claire

Published
2020
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14. OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Author

Celse, Tristan, primary, Tingaud-Sequeira, Angèle, additional, Dieterich, Klaus, additional, Siegfried, Geraldine, additional, Lecaignec, Cédric, additional, Bouneau, Laurence, additional, Fannemel, Madeleine, additional, Salaun, Gaelle, additional, Laffargue, Fanny, additional, Martinez, Guillaume, additional, Satre, Véronique, additional, Vieville, Gaelle, additional, Bidart, Marie, additional, Soussi Zander, Cecilia, additional, Turesson, Ann-Charlotte, additional, Splitt, Miranda, additional, Reboul, Dorothee, additional, Chiesa, Jean, additional, Khau Van Kien, Philippe, additional, Godin, Manon, additional, Gruchy, Nicolas, additional, Goel, Himanshu, additional, Palmer, Elizabeth, additional, Demetriou, Kalliope, additional, Shalhoub, Carolyn, additional, Rooryck, Caroline, additional, and Coutton, Charles, additional

Published
2022
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15. OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Author

Tristan Celse, Angèle Tingaud-Sequeira, Klaus Dieterich, Geraldine Siegfried, Cédric Lecaignec, Laurence Bouneau, Madeleine Fannemel, Gaelle Salaun, Fanny Laffargue, Guillaume Martinez, Véronique Satre, Gaelle Vieville, Marie Bidart, Cecilia Soussi Zander, Ann-Charlotte Turesson, Miranda Splitt, Dorothee Reboul, Jean Chiesa, Philippe Khau Van Kien, Manon Godin, Nicolas Gruchy, Himanshu Goel, Elizabeth Palmer, Kalliope Demetriou, Carolyn Shalhoub, Caroline Rooryck, and Charles Coutton

Subjects
Genetics, Genetics (clinical)
Abstract

BackgroundOculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.MethodsWe described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects ofOTX2overexpression in a zebrafish model.ResultsWe defined a 272 kb minimal common region that only overlaps with theOTX2gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression ofOTX2in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.ConclusionsOur results indicate that properOTX2dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated thatOTX2genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.

Published
2022

17. Clinical and neuroimaging findings in 33 patients with <scp>MCAP</scp> syndrome: A survey to evaluate relevant endpoints for future clinical trials

Author

Florence Petit, Fabienne Giuliano, Juliette Mazereeuw-Hautier, Marjolaine Willems, Christel Thauvin-Robinet, Patricia Blanchet, Laurence Faivre, Elodie Gautier, Anne-Claire Bursztejn, Renaud Touraine, Annick Toutain, Frederico Di Rocco, Maxime Luu, Patrick Edery, Arthur Sorlin, Jean-Luc Alessandri, Nicolas Chassaing, Alice Goldenberg, Christine Chiaverini, Fanny Morice-Picard, Aurore Garde, Stéphanie Arpin, Massimiliano Rossi, Marc Bardou, Claire Nicolas, Gilles Morin, Jenny Cornaton, Cyril Mignot, Christophe Philippe, V. Carmignac, Rodolphe Dard, Joelle Roume, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Pierre Vabres, Didier Lacombe, Diane Doummar, Lucile Pinson, Christine Coubes, Laurent Guibaud, Olivia Boccara, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cutis marmorata, Adolescent, Class I Phosphatidylinositol 3-Kinases, Neuroimaging, Context (language use), Skin Diseases, Vascular, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Genetics, Polymicrogyria, medicine, Humans, PROS, Abnormalities, Multiple, Telangiectasis, Megalencephaly, Child, MCAP syndrome, Genetics (clinical), Chiari malformation, Clinical Trials as Topic, business.industry, Macrocephaly, PIK3CA, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Clinical trial, 030104 developmental biology, Child, Preschool, Postnatal macrocephaly, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Forecasting, Ventriculomegaly
Abstract

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Published
2021
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18. Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series

Author

Marion Lesieur‐Sebellin, Marianne Till, Philippe Khau Van Kien, Bérénice Herve, Nicolas Bourgon, Céline Dupont, Anne‐Claude Tabet, Mathilde Barrois, Aurélie Coussement, Laurence Loeuillet, Eve Mousty, Vuthy Ea, Amal Assal, Laura Mary, Sylvie Jaillard, Claire Beneteau, Claudine Le Vaillant, Charles Coutton, Françoise Devillard, Carole Goumy, Amélie Delabaere, Sylvia Redon, Yves Laurent, Audrey Lamouroux, Jérôme Massardier, Catherine Turleau, Damien Sanlaville, Vincent Cantagrel, Pascale Sonigo, François Vialard, Laurent J. Salomon, Valérie Malan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), AP-HP Hôpital universitaire Robert-Debré [Paris], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Maternité Port-Royal [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHI Poissy-Saint-Germain, CHU Pontchaillou [Rennes], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre hospitalier universitaire de Nantes (CHU Nantes), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe Hospitalier Bretagne Sud (GHBS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Brest (UBO), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Cité (UPCité), Service Obstétrique [CHU Clermont-Ferrand], Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Thérapie guidée par l'image (TGI), and SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)-SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, phenotype mimicking heterozygous, INTELLECTUAL DISABILITY, [SDV]Life Sciences [q-bio], Chromosome Disorders, Trisomy, LONG ARM, brain malformations, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 03 medical and health sciences, Pregnancy, FETUSES, MICROARRAY ANALYSIS, Humans, pathogenic variants, Genetics (clinical), 030304 developmental biology, Retrospective Studies, 0303 health sciences, Virulence, DEVELOPMENTAL DELAY, ABNORMALITIES, 030305 genetics & heredity, Calcium-Binding Proteins, REARRANGEMENTS, Obstetrics and Gynecology, Membrane Proteins, deletions, 3. Good health, NOTCH, Phenotype, DIFFERENTIATION, Chromosomes, Human, Pair 6, Female, MENTAL-RETARDATION
Abstract

International audience; OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Published
2021
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19. A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Author

Marion Aubert-Mucca, Bertrand Chesneau, Maud Langeois, Aurélie Plancke, Sophie Julia, Philippe Khau Van Kien, Bertrand Marcheix, Guillaume Rolland, Yves Dulac, Julie Plaisancié, Thomas Edouard, and Thierry Lavabre-Bertrand

Subjects
Male, Proband, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, MYH11, heritable aortic aneurysm syndrome, QH426-470, Thoracic aortic aneurysm, Clinical Reports, Young Adult, Exon, patent ductus arteriosus, splicing, Ductus arteriosus, medicine, Genetics, Humans, Allele, Ductus Arteriosus, Patent, Molecular Biology, Genetics (clinical), Clinical Report, Aortic Aneurysm, Thoracic, Myosin Heavy Chains, business.industry, Intron, Exons, genotype–phenotype correlation, medicine.disease, Aortic Dissection, medicine.anatomical_structure, Mutation, RNA splicing, RNA Splice Sites, business
Abstract

Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies., We report on a family with heritable thoracic aortic aneurysm and/or dissection with patent ductus arteriosus (FTAAD/PDA) caused by a variant leading to a skipping of the exon 32 in the MYH11 gene. This transcripts defect previously shown to lead to a strong dominant negative effect in the smooth muscle myosin rod is recurrent. It highlights some unclear genotype‐phenotype correlations suggested by literature with some alleles associated with autosomal dominant FTAAD/PDA while others result in recessive visceral myopathies.

Published
2021

21. Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series

Author

Lesieur‐Sebellin, Marion, primary, Till, Marianne, additional, Khau Van Kien, Philippe, additional, Herve, Bérénice, additional, Bourgon, Nicolas, additional, Dupont, Céline, additional, Tabet, Anne‐Claude, additional, Barrois, Mathilde, additional, Coussement, Aurélie, additional, Loeuillet, Laurence, additional, Mousty, Eve, additional, Ea, Vuthy, additional, Assal, Amal, additional, Mary, Laura, additional, Jaillard, Sylvie, additional, Beneteau, Claire, additional, Le Vaillant, Claudine, additional, Coutton, Charles, additional, Devillard, Françoise, additional, Goumy, Carole, additional, Delabaere, Amélie, additional, Redon, Sylvia, additional, Laurent, Yves, additional, Lamouroux, Audrey, additional, Massardier, Jérôme, additional, Turleau, Catherine, additional, Sanlaville, Damien, additional, Cantagrel, Vincent, additional, Sonigo, Pascale, additional, Vialard, François, additional, Salomon, Laurent J., additional, and Malan, Valérie, additional

Published
2021
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22. A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Author

Chesneau, Bertrand, primary, Plancke, Aurélie, additional, Rolland, Guillaume, additional, Marcheix, Bertrand, additional, Dulac, Yves, additional, Edouard, Thomas, additional, Plaisancié, Julie, additional, Aubert‐Mucca, Marion, additional, Julia, Sophie, additional, Langeois, Maud, additional, Lavabre‐Bertrand, Thierry, additional, and Khau Van Kien, Philippe, additional

Published
2021
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23. Author response for 'Clinical and neuroimaging findings in 33 patients with MCAP syndrome: a survey to evaluate relevant endpoints for future clinical trials'

Author

Florence Petit, Juliette Mazereeuw-Hautier, Christine Coubes, Patricia Blanchet, Jenny Cornaton, Frederico Di Rocco, Fabienne Giuliano, Arthur Sorlin, Elodie Gautier, Laurent Guibaud, Renaud Touraine, Massimiliano Rossi, Christophe Philippe, Jean-Luc Alessandri, Joelle Roume, Patrick Edery, Gilles Morin, Christine Chiaverini, Diane Doummar, Michèle Mathieu-Dramard, Olivia Boccara, Philippe Khau Van Kien, Aurore Garde, Claire Nicolas, Maxime Luu, Lucile Pinson, Nicolas Chassaing, Fanny Morice-Picard, Christel Thauvin-Robinet, Rodolphe Dard, Cyril Mignot, Marc Bardou, V. Carmignac, Pierre Vabres, Alice Goldenberg, Laurence Faivre, Didier Lacombe, Annick Toutain, Stéphanie Arpin, Marjolaine Willems, and Anne-Claire Bursztejn

Subjects
Clinical trial, medicine.medical_specialty, Neuroimaging, business.industry, medicine, Intensive care medicine, business
Published
2020
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24. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author

Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract

White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.

Published
2020
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25. Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author

Julien Thevenon, Sophie Blesson, Sylvie Manouvrier Hanu, Chloé Quélin, Florence Fellmann, Nicolas Chassaing, Fabienne Giuliano, Laetitia Lambert, Caroline Rooryck-Thambo, Pierre-Simon Jouk, Sylvie Di Filippo, Alexandre Vasiljevic, Christine Francannet, Daphné Lehalle, Audrey Putoux, Anna‐Gaëlle Giguet‐Valard, Sophie Naudion, Salima El Chehadeh, Estelle Colin, Viorica Ciorna‐Monferrato, Bruno Reversade, Lionel Van Maldergem, Fanny Morice-Picard, Renaud Touraine, Sébastien Moutton, Jocelyne Attia, Laurent Pasquier, A. Vigouroux-Castera, Catherine Yardin, Tania Attié-Bitach, Carine Abel, Hui Liu, Sylvie Odent, Christelle Cabrol, Florence Petit, Philippe Khau Van Kien, Thomas Simonet, Catherine Vincent-Delorme, Jean Chiesa, Juliette Piard, Anne Bazin, Mélanie Fradin, Bertrand Isidor, Loubna El Zein, Patrice Bouvagnet, Marie-Pierre Brechard, Emmanuelle Szenker-Ravi, Sophie Scheidecker, Claire Beneteau, and ACS - Heart failure & arrhythmias

Subjects
Heart Defects, Congenital, Male, midline anomaly, Heterozygote, medicine.medical_specialty, Genetic counseling, Consanguinity, Heterotaxy Syndrome, Biology, DNA sequencing, 03 medical and health sciences, consanguinity, Genetics, medicine, Humans, Family, Family history, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, Obstetrics, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, heterotaxy, congenital heart defects, Cardiac malformations, Pedigree, fetus, Parental consanguinity, Cytogenetic Analysis, Mutation, Female, next-generation sequencing, Heterotaxy
Abstract

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.

Published
2020

26. Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule

Author

Cyril Goizet, Patrick Calvas, Marie-Claire Vincent, Claire Guissart, Virginie Dorian, Nicolas Molinari, Caroline Rooryck-Thambo, Cathy Liautard-Haag, Annabelle Chaussenot, Romain Favre, Catherine Alix-Panabières, Sandra Pierredon, Laetitia Monteil, Philippe Khau Van Kien, Mélanie Fradin, Amandine Boureau-Wirth, Marion Imbert-Bouteille, Emmanuelle Haquet, Elsa Le Boette, Yuliya Petrov, Jacques Puechberty, Cécile Zordan, Céline Moutou, Laure Cayrefourcq, Cécile Rouzier, Marjolaine Willems, Claire Miry, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Strasbourg, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de la Colombière, CHU de Bordeaux Pellegrin [Bordeaux], Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Les Hôptaux universitaires de Strasbourg (HUS), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre hospitalier Saint-Brieuc, and Salvy-Córdoba, Nathalie

Subjects
0301 basic medicine, MESH: Trophoblasts, Molecular biology, lcsh:Medicine, Diseases, Disease, Cell Separation, 0302 clinical medicine, Trinucleotide Repeats, Prenatal Diagnosis, lcsh:Science, MESH: High-Throughput Nucleotide Sequencing, Genetics, Whole Genome Amplification, 030219 obstetrics & reproductive medicine, Multidisciplinary, Molecular medicine, High-Throughput Nucleotide Sequencing, Trophoblasts, Huntington Disease, Microsatellite, Single-Cell Analysis, Biotechnology, MESH: Trinucleotide Repeats, Cell biology, Prenatal diagnosis, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Cell Separation, Article, 03 medical and health sciences, Medical research, Fetus, Multiplex polymerase chain reaction, Humans, Allele, MESH: Prenatal Diagnosis, Genotyping, MESH: Humans, Point mutation, lcsh:R, Health care, MESH: Fetus, MESH: Huntington Disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Feasibility Studies, lcsh:Q, MESH: Feasibility Studies, MESH: Single-Cell Analysis
Abstract

Non-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington’s disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation.

Published
2020
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27. Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Author

Kirsley Chennen, Philippe Loget, Alix Clemenson, Elise Schaefer, Marie-Josée Perez, Elsa Nourisson, Laura Mary, Corinne Stoetzel, Bernard Gasser, Jean Muller, Annie Buenerd, Lucile Pinson, Louise Devisme, Florence Petit, Olivier Poch, Anne Sophie Leuvrey, Fabien Guimiot, Patrice Bouvagnet, Caroline Rooryck-Thambo, Brigitte Leroy, Manuela Antin, Tania Attié-Bitach, Jelena Martinovic, Fanny Pelluard, Raymonde Bouvier, Hélène Dollfus, Brigitte Gilbert-Dussardier, Elisabeth Alanio-Detton, Maria Cristina Antal, and Philippe Khau Van Kien

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Genotype, Biopsy, Autopsy, Disease, 030105 genetics & heredity, 03 medical and health sciences, Bardet–Biedl syndrome, Prenatal Diagnosis, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bardet-Biedl Syndrome, Alleles, Genetic Association Studies, Genetics (clinical), Cystic kidney, Fetus, Polydactyly, business.industry, medicine.disease, Ciliopathy, Phenotype, 030104 developmental biology, Amino Acid Substitution, Mutation, business
Abstract

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Published
2019
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29. Malformations Artérioveineuses

Author

Khau Van Kien, A., primary, Vernhet-Kovasick, H., additional, Bisdorff-Bresson, A., additional, Laroche, J.-P., additional, Bigorre, M., additional, Sirvente, J., additional, and Quéré, I., additional

Published
2011
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30. Liste des auteurs

Author

Aboyans, Victor, primary, Abud, T., additional, Albertini, Jean-Noël, additional, Alhenc-Gelas, Martine, additional, Allaire, Éric, additional, Amar, Laurence, additional, Azema, Laure, additional, Azizi, Michel, additional, Auvert, Jean-François, additional, Avouac, Julien, additional, Aymard, Armand, additional, Barral, Xavier, additional, Barthelemy, Pierre, additional, Baud, Jean-Michel, additional, Baudoin, Patrice, additional, Becker, François, additional, Ben Ahmed, S., additional, Berard, Annie, additional, Bereau, Estelle, additional, Bertoletti, Laurent, additional, Bigorre, Michèle, additional, Biland, Guillaume, additional, Bisdorff-Bresson, Annouk, additional, Blaise, Sophie, additional, Blum, Alain, additional, Böge, Gudrun, additional, Boisseau, Michel Robert, additional, Boissier, Christian, additional, Bonnet, Vincent, additional, Bonnin, Christophe, additional, Bossavy, Jean-Pierre, additional, Bouilly, Patrick, additional, Boulon, Carine, additional, Branchereau, Alain, additional, Bregeaud, Delphine, additional, Bressollette, Luc, additional, Breviere, Georges-Marie, additional, Brisbois, Denis, additional, Brisset, D., additional, Brocheriou, Isabelle, additional, Bruneval, Patrick, additional, Cottentin, Olivier, additional, Bura-Riviere, Alessandra, additional, Cacoub, Patrice, additional, Cambou, Jean-Pierre, additional, Camelot, Gabriel, additional, Carpentier, Patrick, additional, Cauchy, Emmanuel, additional, Chammas, Michel, additional, Chaufour, Xavier, additional, Chiche, Laurent, additional, Clin-Godard, B., additional, Conard, Jacqueline, additional, Connes, Philippe, additional, Conri, Claude, additional, Constans, Joël, additional, Coppé, Gérard, additional, Coulon, Paul, additional, Coupé, Marlène, additional, Cremer, Antoine, additional, Creton, Denis, additional, Creton, Olivier, additional, Dahan, Philippe, additional, Dallongeville, Jean, additional, Dautzenberg, Bertrand, additional, Dauzat, Michel, additional, de Wilde, Jean-Philippe, additional, Debourdeau, Philippe, additional, Debure, Clélia, additional, Decousus, Hervé, additional, Degrullier-Chopinet, Caroline, additional, Dehant, Véronique, additional, Deklunder, Ghyslaine, additional, Delluc, Aurélien, additional, Delsart, Pascal, additional, Diot, Elisabeth, additional, Dulac, Yves, additional, Duprey, Ambroise, additional, Durant, C., additional, Duthois, Sylvain, additional, El Jaouhari, Asma, additional, Elias, Antoine, additional, Elias, Marie, additional, Emmerich, Joseph, additional, Esnault, Vincent, additional, Farge-Bancel, Dominique, additional, Farnier, Michel, additional, Faure, Sébastien, additional, Favre, Jean-Pierre, additional, Ferreira-Maldent, Nicole, additional, Ferrieres, Jean, additional, Fiessinger, Jean-Noël, additional, Flaujac, Claire, additional, Fontana, Pierre, additional, Frank, Michael, additional, Frederic, Muriel, additional, Gagnon, Nathalie, additional, Gardet, Emmanuel, additional, Garrigues, Damien, additional, Gerard, Jean-Luc, additional, Gigou, F., additional, Girerd, Xavier, additional, Goret, Lucie, additional, Gosse, Philippe, additional, Grenier, Nicolas, additional, Grimaldi, André, additional, Guibaud, Laurent, additional, Guillevin, Loïc, additional, Guilmot, Jean-Louis, additional, Haase, Caroline, additional, Hachulla, Éric, additional, Halbron, Marine, additional, Hamel-Desnos, Claudine, additional, Hammel, Jonathan, additional, Hanon, Olivier, additional, Hatron, Pierre-Yves, additional, Hermier, Marc, additional, Horellou, Marie-Hélène, additional, Houdart, Emmanuel, additional, Khau van Kien, Aurélie, additional, Kieffer, Edouard, additional, Koskas, Fabien, additional, Kretz, Jean-Georges, additional, Labau, Diane, additional, Lacroix, Philippe, additional, Lacut, Karine, additional, Laffont, Joëlle-Yvette, additional, Lambert, Marc, additional, Laroche, Jean-Pierre, additional, Larrue, Vincent, additional, Laskar, Marc, additional, Lasry, Jean-Louis, additional, Laurian, Claude, additional, Lazareth, Isabelle, additional, Le Bras, Yann, additional, Le Gal, Grégoire, additional, Le Hello, Claire, additional, Le Thi Huong, D., additional, Lecompte, Thomas, additional, Leftheriotis, Georges, additional, Lemarchand-Venencie, F., additional, Lemasle, Philippe, additional, Letombe, Brigitte, additional, Levesque, Hervé, additional, Long, Anne, additional, Luizy, François (†), additional, Magnan, Pierre-Edouard, additional, Magnant, Julie, additional, Mallios, A., additional, Marchand-Adam, Sylvain, additional, Marie, Isabelle, additional, Martinez, Carmen, additional, Maumias, T., additional, Meaume, Sylvie, additional, Messas, Emmanuel, additional, Mestre, Sandrine, additional, Meyer, Guy, additional, Midy, Dominique, additional, Mismetti, Patrick, additional, Mollard, Jean-Marc, additional, Montaudon, Michel, additional, Moraglia, Luc, additional, Mottier, Dominique, additional, Mounier-Vehier, Claire, additional, Moyou-Mogo, Roger, additional, Nicolini, Philippe, additional, Nourrissat, Ghislain, additional, Ouvry, Pierre, additional, Patra, Philippe, additional, Perez Martin, Antonia, additional, Pernes, Jean-Marc, additional, Pernod, Gilles, additional, Perret-Guillaume, Christine, additional, Perrin, Michel, additional, Pesteil, Francis, additional, Pichot, Olivier, additional, Pistorius, Marc-Antoine, additional, Planchon, Bernard, additional, Plouin, Pierre-François, additional, Poggi, Jean-Noël, additional, Priollet, Pascal, additional, Quehe, Philippe, additional, Quere, Isabelle, additional, Ramelet, Albert-Adrien, additional, Renaudin, Jean-Marc, additional, Reny, Jean-Luc, additional, Righini, Marc, additional, Rosenbaum, David, additional, Rosset, Eugenio, additional, Roy, Pierre-Marie, additional, Saadi, Leilah, additional, Saby, Jean-Claude, additional, Samama, Meyer Michel, additional, Sandrin-Berthon, Brigitte, additional, Satger-Gouin, Bernardette, additional, Iris, Schuster-Beck, additional, Segard, Magali, additional, Sene, Damien, additional, Senet, Patricia, additional, Serise, Jean Michel, additional, Sessa, Carmine, additional, Sevestre-Pietri, Marie-Antoinette, additional, Sirvente, Jérôme, additional, Solanilla, Anne, additional, Soulier-Sotto, Virginie, additional, Sprynger, Muriel, additional, Stephan, Dominique, additional, Sussman, Hélène, additional, Tanguy, Bénédicte, additional, Terriat, Béatrice, additional, Thiebaugeorges, Olivier, additional, Thomas, Daniel, additional, Tribout, Laurent, additional, Turpault, Jean-Philippe, additional, Vaillant, Loïc, additional, Van Cleef, Jean-François, additional, Vayssairat, Michel, additional, Vernhet-Kovasick, Hélène, additional, Vicaut, Éric, additional, Vignes, Stéphane, additional, Villeneuve, Frédéric, additional, Viremouneix, Loïc, additional, Wahl, Denis, additional, Warembourg, Frédérique, additional, Wautrecht, Jean-Claude, additional, Wechsler, Bertrand, additional, and Zuily, Stéphane, additional

Published
2011
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33. OTX2duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Author

Celse, Tristan, Tingaud-Sequeira, Angèle, Dieterich, Klaus, Siegfried, Geraldine, Lecaignec, Cédric, Bouneau, Laurence, Fannemel, Madeleine, Salaun, Gaelle, Laffargue, Fanny, Martinez, Guillaume, Satre, Véronique, Vieville, Gaelle, Bidart, Marie, Soussi Zander, Cecilia, Turesson, Ann-Charlotte, Splitt, Miranda, Reboul, Dorothee, Chiesa, Jean, Khau Van Kien, Philippe, Godin, Manon, Gruchy, Nicolas, Goel, Himanshu, Palmer, Elizabeth, Demetriou, Kalliope, Shalhoub, Carolyn, Rooryck, Caroline, and Coutton, Charles

Abstract

BackgroundOculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.MethodsWe described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2overexpression in a zebrafish model.ResultsWe defined a 272 kb minimal common region that only overlaps with the OTX2gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.ConclusionsOur results indicate that proper OTX2dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.

Published
2023
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34. Liste des Auteurs

Author

Constans, Joël, primary, Aboyans, Victor, additional, Abud, T., additional, Albertini, Jean-Noël, additional, Alhenc-Gelas, Martine, additional, Allaire, Eric, additional, Amar, Laurence, additional, Azema, Laure, additional, Azizi, Michel, additional, Auvert, Jean-François, additional, Avouac, Julien, additional, Aymard, Armand, additional, Barral, Xavier, additional, Barthelemy, Pierre, additional, Baud, Jean-Michel, additional, Hôpital, André Mignot, additional, Baudoin, Patrice, additional, Becker, François, additional, Ben Ahmed, S., additional, Berard, Annie, additional, Bereau, Estelle, additional, Bertoletti, Laurent, additional, Bigorre, Michèle, additional, Biland, Guillaume, additional, Bisdorff-Bresson, Annouk, additional, Blaise, Sophie, additional, Blum, Alain, additional, Böge, Gudrun, additional, Boisseau, Michel R., additional, Boissier, Christian, additional, Bonnet, Vincent, additional, Bonnin, Christophe, additional, Bossavy, Jean-Pierre, additional, Bouilly, Patrick, additional, Boulon, Carine, additional, Branchereau, Alain, additional, Bregeaud, Delphine, additional, Bressollette, Luc, additional, Breviere, Georges-Marie, additional, Brisbois, Denis, additional, Brisset, D., additional, Brocheriou, Isabelle, additional, Bruneval, Patrick, additional, Bura-Riviere, Alessandra, additional, Cacoub, Patrice, additional, Cambou, Jean-Pierre, additional, Camelot, Gabriel, additional, Carpentier, Patrick, additional, Cauchy, Emmanuel, additional, Chammas, Michel, additional, Chaufour, Xavier, additional, Chiche, Laurent, additional, Clin-Godard, Bénédicte, additional, Conard, Jacqueline, additional, Connes, Philippe, additional, Conri, Claude, additional, Constans, Joël, additional, Coppé, Gérard, additional, Cottentin, Olivier, additional, Coulon, Paul, additional, Coupé, Marlène, additional, Cremer, Antoine, additional, Creton, Denis, additional, Creton, Olivier, additional, Dahan, Philippe, additional, Dallongeville, Jean, additional, Dautzenberg, Bertrand, additional, Dauzat, Michel, additional, De Wilde, Jean-Philippe, additional, Debourdeau, Philippe, additional, Debure, Clélia, additional, Decousus, Hervé, additional, Degrullier-Chopinet, Caroline, additional, Dehant, Véronique, additional, Deklunder, Ghyslaine, additional, Delluc, Aurélien, additional, Delsart, Pascal, additional, Diot, Elisabeth, additional, Dulac, Yves, additional, Duprey, Ambroise, additional, Durant, C., additional, Duthois, Sylvain, additional, El Jaouhari, Asma, additional, Elias, Antoine, additional, Elias, Marie, additional, Emmerich, Joseph, additional, Esnault, Vincent, additional, Farge-Bancel, Dominique, additional, Farnier, Michel, additional, Faure, Sébastien, additional, Favre, Jean-Pierre, additional, Ferreira-Maldent, Nicole, additional, Ferrieres, Jean, additional, Fiessinger, Jean-Noel, additional, Flaujac, Claire, additional, Fontana, Pierre, additional, Frank, Michael, additional, Frederic, Muriel, additional, Gagnon, Nathalie, additional, Gardet, Emmanuel, additional, Garrigues, Damien, additional, Gerard, Jean-Luc, additional, Gigou, Frédéric, additional, Girerd, Xavier, additional, Goret, Lucie, additional, Gosse, Philippe, additional, Grenier, Nicolas, additional, Grimaldi, André, additional, Guibaud, Laurent, additional, Guillevin, Loïc, additional, Guilmot, Jean-Louis, additional, Haase, Caroline, additional, Hachulla, Eric, additional, Halbron, Marine, additional, Hamel-Desnos, Claudine, additional, Hammel, Jonathan, additional, Hanon, Olivier, additional, Hatron, Pierre-Yves, additional, Hermier, Marc, additional, Horellou, Marie-Hélène, additional, Houdart, Emmanuel, additional, Khau Van Kien, Aurélie, additional, Kieffer, Edouard, additional, Koskas, Fabien, additional, Kretz, Jean-Georges, additional, Labau, Diane, additional, Lacroix, Philippe, additional, Lacut, Karine, additional, Laffont, Joëlle-Yvette, additional, Lambert, Marc, additional, Chru, de Lille, additional, Laroche, Jean-Pierre, additional, Larrue, Vincent, additional, Laskar, Marc, additional, Laurian, Claude, additional, Lazareth, Isabelle, additional, Le Bras, Yann, additional, Le Gal, Grégoire, additional, Le Hello, Claire, additional, Le Thi Huong, Du, additional, Lecompte, Thomas, additional, Leftheriotis, Georges, additional, Lemarchand-Venencie, Françoise, additional, Lemasle, Philippe, additional, Letombe, Brigitte, additional, Levesque, Hervé, additional, Long, Anne, additional, Luizy, François, additional, Magnan, Pierre-Edouard, additional, Magnant, Julie, additional, Mallios, Alexandros, additional, Marchand-Adam, Sylvain, additional, Marie, Isabelle, additional, Martinez, Carmen, additional, Maumias, Thibault, additional, Meaume, Sylvie, additional, Messas, Emmanuel, additional, Mestre, Sandrine, additional, Meyer, Guy, additional, Midy, Dominique, additional, Mismetti, Patrick, additional, Mollard, Jean-Marc, additional, Montaudon, Michel, additional, Moraglia, Luc, additional, Mottier, Dominique, additional, Mounier-Vehier, Claire, additional, Moyou-Mogo, Roger, additional, Nicolini, Philippe, additional, Nourrissat, Ghislain, additional, Ouvry, Pierre, additional, Patra, Philippe, additional, Perez Martin, Antonia, additional, Pernes, Jean-Marc, additional, Pernod, Gilles, additional, Perret-Guillaume, Christine, additional, Perrin, Michel, additional, Pesteil, Francis, additional, Pichot, Olivier, additional, Pistorius, Marc-Antoine, additional, Planchon, Bernard, additional, Plouin, Pierre-François, additional, Poggi, Jean-Noël, additional, Priollet, Pascal, additional, Quehe, Philippe, additional, Quere, Isabelle, additional, Ramelet, Albert-Adrien, additional, Renaudin, Jean-Marc, additional, Reny, Jean-Luc, additional, Righini, Marc, additional, Rosenbaum, David, additional, Rosset, Eugenio, additional, Roy, Pierre-Marie, additional, Saadi, Leilah, additional, Saby, Jean-Claude, additional, Samama, Meyer Michel, additional, Sandrin-Berthon, Brigitte, additional, Satger-Gouin, Bernardette, additional, Schuster-Beck, Iris, additional, Chu, de Montpellier, additional, Segard, Magali, additional, Sene, Damien, additional, Senet, Patricia, additional, Serise, Jean Michel, additional, Sessa, Carmine, additional, Sevestre-Pietri, Marie-Antoinette, additional, Sirvente, Jérôme, additional, Solanilla, Anne, additional, Soulier-Sotto, Virginie, additional, Sprynger, Muriel, additional, Stephan, Dominique, additional, Sussman, Hélène, additional, Tanguy, Bénédicte, additional, Terriat, Béatrice, additional, Thiebaugeorges, Olivier, additional, Thomas, Daniel, additional, Tribout, Laurent, additional, Turpault, Jean-Philippe, additional, Vaillant, Loïc, additional, Van Cleef, Jean-François, additional, Vayssairat, Michel, additional, Vernhet-Kovasick, Hélène, additional, Vicaut, Eric, additional, Vignes, Stéphane, additional, Villeneuve, Frédéric, additional, Viremouneix, Loïc, additional, Wahl, Denis, additional, Warembourg, Frédérique, additional, Wautrecht, Jean Claude, additional, Wechsler, Bertrand, additional, and Zuily, Stéphane, additional

Published
2010
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35. Syndrome d’Ehlers-Danlos vasculaire

Author

Perdu, Jérôme, Boutouyrie, Pierre, Lahlou-Laforêt, Khadija, Khau Van Kien, Philippe, Denarié, Nicolas, Mousseaux, Elie, Sapoval, Marc, Julia, Pierre, Zinzindohoué, Frank, Touraine, Philippe, Dumez, Yves, Trystram, Denis, Vignal-Clermont, Catherine, Gimenez-Roqueplo, Anne-Paule, Jeunemaitre, Xavier, and Fiessinger, Jean-Noël

Published
2006
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37. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author

Garde, Aurore, primary, Cornaton, Jenny, additional, Sorlin, Arthur, additional, Moutton, Sébastien, additional, Nicolas, Claire, additional, Juif, Christine, additional, Geneviève, David, additional, Perrin, Laurence, additional, Khau‐Van‐Kien, Philippe, additional, Smol, Thomas, additional, Vincent‐Delorme, Catherine, additional, Isidor, Bertrand, additional, Cogné, Benjamin, additional, Afenjar, Alexandra, additional, Keren, Boris, additional, Coubes, Christine, additional, Prieur, Fabienne, additional, Toutain, Annick, additional, Trousselet, Yann, additional, Bourgouin, Solène, additional, Gonin‐Olympiade, Coralie, additional, Giraudat, Kim, additional, Piton, Amélie, additional, Gérard, Bénédicte, additional, Odent, Sylvie, additional, Tessier, Fanny, additional, Lemasson, Lola, additional, Heide, Solveig, additional, Gelineau, Anne‐Claire, additional, Sarret, Catherine, additional, Miret, Anne, additional, Schaefer, Elise, additional, Piard, Juliette, additional, Mathevet, Rémi, additional, Boucon, Marion, additional, Bruel, Ange‐Line, additional, Mau‐Them, Frederic Tran, additional, Chevarin, Martin, additional, Vitobello, Antonio, additional, Philippe, Christophe, additional, Thauvin‐Robinet, Christel, additional, and Faivre, Laurence, additional

Published
2020
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38. Next‐generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy

Author

Liu, Hui, primary, Giguet‐Valard, Anna‐Gaëlle, additional, Simonet, Thomas, additional, Szenker‐Ravi, Emmanuelle, additional, Lambert, Laetitia, additional, Vincent‐Delorme, Catherine, additional, Scheidecker, Sophie, additional, Fradin, Mélanie, additional, Morice‐Picard, Fanny, additional, Naudion, Sophie, additional, Ciorna‐Monferrato, Viorica, additional, Colin, Estelle, additional, Fellmann, Florence, additional, Blesson, Sophie, additional, Jouk, Pierre‐Simon, additional, Francannet, Christine, additional, Petit, Florence, additional, Moutton, Sébastien, additional, Lehalle, Daphné, additional, Chassaing, Nicolas, additional, El Zein, Loubna, additional, Bazin, Anne, additional, Bénéteau, Claire, additional, Attié‐Bitach, Tania, additional, Hanu, Sylvie M., additional, Brechard, Marie‐Pierre, additional, Chiesa, Jean, additional, Pasquier, Laurent, additional, Rooryck, Caroline, additional, Van Maldergem, Lionel, additional, Cabrol, Christelle, additional, El Chehadeh, Salima, additional, Vasiljevic, Alexandre, additional, Isidor, Bertrand, additional, Abel, Carine, additional, Thevenon, Julien, additional, Di Filippo, Sylvie, additional, Vigouroux‐Castera, Adeline, additional, Attia, Jocelyne, additional, Quelin, Chloé, additional, Odent, Sylvie, additional, Piard, Juliette, additional, Giuliano, Fabienne, additional, Putoux, Audrey, additional, Khau Van Kien, Philippe, additional, Yardin, Catherine, additional, Touraine, Renaud, additional, Reversade, Bruno, additional, and Bouvagnet, Patrice, additional

Published
2020
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39. Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function

Author

Pierre Clerson, Aurélie Khau Van Kien, Alice Bérezné, Virginie Gressin, Christian Agard, Catherine Lok, Patrick Jego, Luc Mouthon, Agnès Sparsa, Elisabeth Diot, Anne-Bénédicte Duval-Modeste, Eve Puzenat, Patrick H. Carpentier, Marie-Aleth Richard, and Eric Hachulla

Subjects
Adult, Endothelin Receptor Antagonists, Male, medicine.medical_specialty, Visual analogue scale, Disease, Severity of Illness Index, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Quality of life, Internal medicine, Skin Ulcer, medicine, Clinical endpoint, Humans, In patient, Prospective Studies, 030212 general & internal medicine, Aged, 030203 arthritis & rheumatology, Sulfonamides, Scleroderma, Systemic, Hand function, business.industry, Bosentan, Middle Aged, Hand, Surgery, Treatment Outcome, Anesthesiology and Pain Medicine, Quality of Life, Female, Observational study, business, medicine.drug
Abstract

Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan.ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up.Data were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046).In patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability.

Published
2017
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40. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Author

Florence Petit, Clémence Vanlerberghe, Thomas Smol, Fabienne Giuliano, M.F. Odou, Sylvie Manouvrier-Hanu, Perrine Brunelle, William Dufour, Malika Balduyck, Fabienne Escande, Jamal Ghoumid, Marion Gérard, Philippe Khau Van Kien, Gilles Morin, Cindy Colson, Alice Goldenberg, Elise Brischoux-Boucher, Anne Dieux, Daphné Lehalle, Anne-Sophie Jourdain, Sébastien Moutton, Simon Boussion, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de dynamique des systèmes neuroendocriniens, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Laboratoire Pierre Süe (LPS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Inserm, Université de Lille, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Maladies RAres du DÉveloppement embryonnaire et du Métabolisme : du phénotype au génotype et à la Fonction (RADEME) - ULR 7364, CIC CHU ( Lille)/inserm, Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Service de Génétique Clinique [CHU Caen], Université de Lausanne = University of Lausanne [UNIL], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME], and Richard, Nicolas

Subjects
Male, Candidate gene, limb malformation, molecular diagnosis, targeted high-throughput sequencing, genetics, DNA Copy Number Variations, DNA Mutational Analysis, Limb Deformities, Congenital, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Real-Time Polymerase Chain Reaction, Bioinformatics, DNA sequencing, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Multiplex, Genetic Testing, Uncertain significance, Gene, Alleles, Genetic Association Studies, Genetics (clinical), Likely pathogenic, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Phenotype, 3. Good health, Radiography, Clinical Practice, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female
Abstract

International audience; Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high-throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3-year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy-number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high-throughput sequencing works as an efficient and cost-effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.

Published
2020
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41. A Broad Test Based on Fluorescent-Multiplex PCR for Noninvasive Prenatal Diagnosis of Cystic Fibrosis

Author

Claire Guissart, Victoria Viart, Eric Bieth, Anne Girardet, Cécile Rouzier, Marie-Claire Vincent, Vanessa Debant, Mireille Claustres, Philippe Khau Van Kien, Emmanuelle Haquet, Caroline Raynal, Marie-Pierre Brechard, Frédéric Tran Mau Them, Michel Koenig, Jacques Puechberty, Charlotte Dubucs, Victoria Pritchard, Amandine Boureau-Wirth, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Florida [Gainesville] (UF), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Montpellier, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and CHU Toulouse [Toulouse]

Subjects
Embryology, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Prenatal diagnosis, Locus (genetics), Bioinformatics, Cystic fibrosis, p.Phe508del, 03 medical and health sciences, 0302 clinical medicine, Cell-free fetal DNA, Prenatal Diagnosis, Multiplex polymerase chain reaction, medicine, Humans, Radiology, Nuclear Medicine and imaging, 030212 general & internal medicine, Allele, 030219 obstetrics & reproductive medicine, business.industry, Haplotype, Haplotyping, Obstetrics and Gynecology, General Medicine, Multiplex PCR, medicine.disease, 3. Good health, Haplotypes, Pediatrics, Perinatology and Child Health, Microsatellite, business, Cell-Free Nucleic Acids, Multiplex Polymerase Chain Reaction, Noninvasive prenatal diagnosis
Abstract

Background: Analysis of cell-free fetal DNA in maternal plasma is very promising for early diagnosis of monogenic diseases. However, it has been limited by the need to set up patient- or disease-specific custom-made approaches. Here we propose a universal test based on fluorescent multiplex PCR and size fragment analysis for an indirect diagnosis of cystic fibrosis (CF). Methods: The test, based on haplotyping, includes nine intra- and extragenic short tandem repeats of the CFTR locus, the coamplification of p.Phe508del (the most frequent mutation in CF patients worldwide), and a specific SRY sequence. The assay is able to determine the inherited paternal allele. Results: Our simple approach was successfully applied to 30 couples and provided clear results from the maternal plasma. The mean rate of informative markers was sufficient to propose it for use in indirect diagnosis. Conclusions: This noninvasive prenatal diagnosis test, focused on indirect diagnosis of CF, offers many advantages over current methods: it is simple, rapid, and cost-effective. It allows for the testing of a large number of couples with high risk of CF, whatever the familial mutation of the CFTR gene. It provides an alternative method to reduce the number of invasive tests.

Published
2019
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44. Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

Author

Lesieur‐Sebellin, Marion, Till, Marianne, Khau Van Kien, Philippe, Herve, Bérénice, Bourgon, Nicolas, Dupont, Céline, Tabet, Anne‐Claude, Barrois, Mathilde, Coussement, Aurélie, Loeuillet, Laurence, Mousty, Eve, Ea, Vuthy, El Assal, Amal, Mary, Laura, Jaillard, Sylvie, Beneteau, Claire, Le Vaillant, Claudine, Coutton, Charles, Devillard, Françoise, and Goumy, Carole

Abstract

Objective: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype‐genotype correlations. Method: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. Results: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. Conclusion: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations. Key points: What's already known about this topic?The prenatal ultrasound features of terminal 6q deletions are not well known What does this study add?We report on a series of 22 fetuses. Cerebellar hypoplasia, ventriculomegaly, and anomalies of the corpus callosum are the most frequent ultrasound findings detected in the fetuses. Furthermore, this study highlights the crucial role of the DLL1 gene in brain anomalies and underlines the importance of chromosomal microarray analysis to search for 6q27 microdeletion involving this gene [ABSTRACT FROM AUTHOR]

Published
2022
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45. Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Author

Chesneau, Bertrand, primary, Edouard, Thomas, additional, Dulac, Yves, additional, Colineaux, Hélène, additional, Langeois, Maud, additional, Hanna, Nadine, additional, Boileau, Catherine, additional, Arnaud, Pauline, additional, Chassaing, Nicolas, additional, Julia, Sophie, additional, Jondeau, Guillaume, additional, Plancke, Aurélie, additional, Khau Van Kien, Philippe, additional, and Plaisancié, Julie, additional

Published
2020
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47. Author response for 'Bardet-Biedl syndrome - antenatal presentation of 45 fetuses with biallelic pathogenic variants in known BBS genes'

Author

Louise Devisme, E. Alanio-Detton, Anne Sophie Leuvrey, Kirsley Chennen, Raymonde Bouvier, Hélène Dollfus, Olivier Poch, Elsa Nourisson, Brigitte Gilbert-Dussardier, Fabien Guimiot, Maria Cristina Antal, Patrice Bouvagnet, Laura Mary, Lucile Pinson, Bernard Gasser, Jean Muller, Jelena Martinovic, Manuela Antin, Annie Buenerd, Tania Attié-Bitach, Corinne Stoetzel, Alix Clemenson, C. Rooryck, Philippe Loget, Fanny Pelluard, Elise Schaefer, P. Khau Van Kien, Brigitte Leroy, Florence Petit, and Marie-Josée Perez

Subjects
Fetus, Bardet–Biedl syndrome, business.industry, Medicine, Presentation (obstetrics), business, Bioinformatics, medicine.disease, Gene
Published
2018
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48. Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome

Author

Charlene Chaix, Guillaume Taieb, Sabrina Sacconi, Catherine Vovan, Gaël Cristofari, Nicolas Lévy, Rafaëlle Bernard, Philippe Khau Van Kien, André Maues De Paula, Nadira Lagha, Matteo Garibaldi, Dimitri Renard, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, gain of function mutation, Polyadenylation, Chromosomal Proteins, Non-Histone, facioscapulohumeral muscular dystrophy type 2, [SDV]Life Sciences [q-bio], pair 18, 0302 clinical medicine, chromosomal proteins, Facioscapulohumeral muscular dystrophy, 18p deletion syndrome, humans, Genetics (clinical), Derepression, Genetics, chromosome deletion, facioscapulohumeral, Muscular Dystrophy, Facioscapulohumeral, chromosome disorders, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, intellectual disability, muscle biopsy, MRI, homeodomain proteins, muscular dystrophy, musculoskeletal diseases, chromosomes, congenital, hereditary, and neonatal diseases and abnormalities, inflammatory, Biology, 03 medical and health sciences, DUX4, male, Chromosome 18, non-histone, medicine, biopsy, Epigenetics, human, Gene, medicine.disease, nervous system diseases, 030104 developmental biology, Chromosome 4, hypomethylation, mri, adolescent, chromatin, epigenomics, rna 3' polyadenylation signals, Chromosomes, Human, Pair 18, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Facioscapulohumeral muscular dystrophy (FSHD) has been shown to be related to genetic and epigenetic derepression of DUX4 (mapping to chromosome 4), a gene located within a repeat array of D4Z4 sequences of polymorphic length. FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18). Both FSHD types require permissive polyadenylation signal (4qA) downstream of the D4Z4 array.

Published
2018
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49. ATP6V0A2-related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

Author

Smail Hadj-Rabia, Marc Vasse, Christine Bodemer, Bert Callewaert, Sofie Symoens, Philippe Khau Van Kien, Aicha Salhi, Helen Cox, Aude Beyens, Najoua Kahloul, Elif Yilmaz Gulec, Ester Moreno-Artero, Gonul Ogur, Annie Harroche, Alper Gezdirici, and Ondokuz Mayıs Üniversitesi

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Glycosylation, Dermatology, Hemorrhagic Disorders, Biochemistry, Cataract, Cutis Laxa, Pathogenesis, 030207 dermatology & venereal diseases, 03 medical and health sciences, Consanguinity, Young Adult, 0302 clinical medicine, elastic fiber disarray, von Willebrand disease type 2, Von Willebrand disease, Medicine, Humans, Child, pulmonary emphysema, Molecular Biology, Aged, Skin, Emphysema, Adult patients, business.industry, Elastic fibre, medicine.disease, Elastic Tissue, Phenotype, Wrinkly skin, Elastic fibres, Proton-Translocating ATPases, 030104 developmental biology, Codon, Nonsense, Child, Preschool, Face, Female, RNA Splice Sites, Agenesis of Corpus Callosum, business, Protein Processing, Post-Translational, management, Cutis laxa
Abstract

Gezdirici, Alper/0000-0002-2432-9279; Gezdirici, Alper/0000-0002-2432-9279; vasse, marc/0000-0002-8784-7209; Beyens, Aude/0000-0003-0231-6861 WOS: 000493185700008 PubMed: 29952037 In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa. Special Research Fund of Ghent UniversityGhent University [01N04516]; Scientific Research Fund - Flanders

Published
2018

50. Clinical and genetic data of 20 new patients with SMAD3 mutations type 3 Loeys Dietz syndrome (LDS) and reviews of the literature

Author

Bertrand Chesneau, P. Khau Van Kien, Clément Karsenty, Julie Plaisancié, Yves Dulac, R. Vincent, Thomas Edouard, and A. Guitarte

Subjects
Aortic dissection, Connective Tissue Disorder, medicine.medical_specialty, business.industry, medicine.disease, Loeys–Dietz syndrome, Penetrance, Aortic aneurysm, Dissection, Internal medicine, cardiovascular system, medicine, Cardiology, Missense mutation, Age of onset, Cardiology and Cardiovascular Medicine, business
Abstract

Background Pathogenic variants in SMAD3 (type 3 LDS, Marfan-like connective tissue disorder) cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Generally, these aggressive vascular damages are associated with multisystemic signs including skeletal abnormalities and premature osteoarthritis. Variable expressivity and incomplete penetrance are commonly associated. Methods Aortic status, events, and clinical features were abstracted through retrospective review of medical records 20 new patients (28.8 years-old (6–60)) from 8 families from our Reference Centre. After a complete review of the literature, we collected a total of 49 unique variants of different nature (missense, truncating and splicing variants) from 152 individuals of 58 unrelated families. The aim of this study was to look for genotype-phenotype correlations between the mutations of this gene and the severity of the phenotype. Results Aortic aneurysm and/or dissection are the main vascular findings, affecting respectively 57% and 32% of all type 3 LDS patients described. In our cohort of patients, half presents an aortic dilatation (10/20), 10% an aortic dissection. Three of our patients displays an aortic dilatation during their childhood (at 8 and 7 years old and a surgery for an aortic dilation at 10 years old). Aneurysms and dissections can also be seen in other arteries in 27% (35/138) and particularly intracranial aneurysms found in 20% of patients (21/103), like in two of our patients, one presented an iliac artery dissection. Arterial tortuosity is also frequent, particularly in carotids, representing about a third of the patients (36/117 = 31%), 2 of our 8 patients. Conclusions SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. We confirmed that there is no correlation between the mutation type and the phenotype severity. Aneurysms-Osteoarthritis syndrome (AOS), genotype-phenotype correlation, heritable thoracic aortic aneurysms and dissections (hTAAD), Loeys-Dietz syndrome, SMAD3, Marfan-like connective tissue disorder, TGFβ pathway.

Published
2019
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